Association between Medications That Relax the Lower Esophageal Sphincter and Risk for Esophageal Adenocarcinoma

  1. Jesper Lagergren, MD, PhD;
  2. Reinhold Bergström, PhD;
  3. Hans-Olov Adami, MD, PhD; and
  4. Olof Nyrén, MD, PhD
  1. From Karolinska Institutet and Danderyd Hospital, Stockholm, Sweden; Uppsala University, Uppsala, Sweden; and Harvard Center for Cancer Prevention, Harvard University, Boston, Massachusetts.

    Abstract

    Background: The incidence of esophageal adenocarcinoma is increasing rapidly. Gastroesophageal reflux is a strong risk factor for this disease. The increase in incidence of esophageal adenocarcinoma coincided with the introduction of medications that promote reflux by relaxing the lower esophageal sphincter (LES), such as nitroglycerin, anticholinergics, β-adrenergic agonists, aminophyllines, and benzodiazepines.

    Objective: To test the possible association between use of LES-relaxing medications and risk for adenocarcinoma of the esophagus and gastric cardia.

    Design: A nationwide population-based case–control study with in-person interviews.

    Setting: Sweden, 1995 through 1997.

    Patients: 189 patients with newly diagnosed esophageal adenocarcinoma, 262 with adenocarcinoma of the gastric cardia, and 167 with esophageal squamous-cell carcinoma were compared with 820 population-based controls.

    Measurements: Estimated incidence rate ratios, calculated by using multivariate logistic regression from case–control data with adjustment for potential confounding.

    Results: Past use of LES-relaxing drugs was positively associated with risk for esophageal adenocarcinoma. Among daily, long-term users (>5 years) of LES-relaxing drugs, the estimated incidence rate ratio was 3.8 (95% CI, 2.2 to 6.4) compared with persons who had never used these drugs. Drugs of all classes contributed to the increased risk, but the association was particularly strong for anticholinergics. Short-term use of other types of LES-relaxing drugs did not seem to be strongly associated with risk. The association almost disappeared after adjustment for reflux symptoms, indicating that promotion of reflux is the link between use of LES-relaxing drugs and esophageal adenocarcinoma. If 15 490 men in any age group take LES-relaxing drugs daily for 5 years, 1 additional case of adenocarcinoma would be expected (number needed to treat for harm); in men older than 60 years of age, the number needed to treat for harm is 5570. Assuming a causal relation, about 10% of the esophageal adenocarcinomas occurring in the population may be attributable to intake of LES-relaxing drugs. Cardia adenocarcinoma and esophageal squamous-cell carcinoma were not associated with use of LES-relaxing drugs.

    Conclusions: The widespread use of LES-relaxing drugs may have contributed to the increasing incidence of esophageal adenocarcinoma.

    Article and Author Information

    • † Deceased.

    • Acknowledgments: The authors thank Leila Nyrén for coordination of the field work, Dr. Anders Lindgren for review of all histopathological material, and Dr. Wolfgang Kraaz for expert pathology guidance in the planning of the study and during the field work. They also thank the physicians who acted as contact persons at the participating departments: Bengt Åberg, Bo Ahlman, Örjan Ahrenstedt, Leif-Åke Åkesson, Stig-Olof Almgren, Per Almqvist, Mathias Ålund, Nils-Axel Alsén, Anders Alwmark, Christer Andersson, Lars Andréasson, Ulf Angerås, Åke Arwidi, Lars Backman, Björn Bäckstrand, Mikael Bech, Jan Bergman, Magnus Berne, Hlödur Bjarnasson, Anders Bjerkhed, Jan-Inge Björnberg, John Blomberg, Bernt Boeryd, Paul Boisen, Lars Boman, Anders Borgström, Mogens Bove, Mats Broberg, Stefan Cajander, Tora Cambell-Chiru, Hans Danielsson, Hilmi DeSai, Jan Dolata, Kent Edin, Roger Edin, Bengt Ekelund, Tom Ekstrand, Per Ekström, Lars-Krister Enander, Lennart Engström, Kerstin Erhart, Lars Eriksson, Thomas Eriksson, Sven-Börje Ewers, Jan Fagerberg, Mats Fagerberg, Anders Falk, Anders Faxén, Mats Fernström, Wolfgang Finkbeiner, Björn Fornander, Nils Forsby, Ulla Friberg, Kjell Furugård, Adel Gad, Ann Gawelin, Ole Grangaard, Lars Granström, Per Gullstrand, Olle Gunder, Peter Gunvén, Gunnar Gustafsson, Gustav Gustavsson, Hans Gustavsson, Sven Gustavsson, Göran Göransson, Mehmet Gözen, Tomas Hagerman, Ulf Haglund, Bengt Hallerbäck, Göran Hambreus, Erik Hammar, Ann Hammarlund, Lars-Erik Hammrström, Göran Hansson, Lennart Hardell, Lennart Hedenborg, Per Herlin, Ivar Holmgren, Lars-Erik Holmgren, Hans-Olof Håkansson, Claes Höglund, Hans Högström, Ulf Hyvönen, Gunnar Isaksson, Elisabeth Jansson, Roland Jansson, Pål-Henry Jeppsson, Karl-Erik Johansson, Leif Johansson, Sven Johansson, Göran Karlsson, Antii Kempas, Staffan Kinman, Ingvar Kjartanson, Gerhard Kjellén, Arne Kleberg, Per-Arne Kling, Jan Klos, Wieslava Krauze, Richard Kuylenstierna, Anders Kylebäck, Fredrik Kylberg, Peter Lannes, Lars-Göran Larsson, Sven Larsson, Carl-Erik Leijonmark, Freddi Lewin, Pontus Lidberg, Håkan Liljeholm, Tore Lind, Sten-Åke Lindahl, Jacob Lindhagen, Christer Lindholm, Karin Lindholm, Thomas Linné, Otto Ljungberg, Martin Ljungman, Mikael Ljungdahl, Thomas Lorenz, Bertil Lundberg, Kjell Lundberg, Sven Lundberg, Lars Lundell, Jan Lundgren, Lars Lundgren, Helge Lyckberg, Tord Magnusson, Jan Malina, Lennart Mannerberg, Joachim Mark, Janusz Matusik, Lennart Mellbom, Claes Mercke, Anders Moberg, Hans Modig, Eva Munck-Wikland, Ewa Mårtensson, Ingemar Näslund, Arthur Nathanson, Torben Navne, Anders Nihlberg, Klas Nilsell, Erik Nilsson, Kjell Nilsson, Lars Nilsson, Mats Nilsson, Ola Nilsson, Roland Nilsson, Arne Nordahl, Torgny Nordén, Bo Nordenskjöld, Stefan Öberg, Bengt Ohlander, Hans Öhman, Jan Öhman, Bo Ojen, Bengt Olsson, Håkan Olsson, Olle Olsson, Jan Oscarsson, Åke Öst, Görel Östberg, Jan Ovesen, Roland Pahlitzsch, Carl-Magnus Peterson, Karl-Iver Pettersson, Peter Pitkänen, Göran Rådberg, Ture Rådmark, Stig Ramel, Gunnar Rimsbäck, Björn Risberg, Jörgen Roed, Staffan Rosendahl, Sam Rotstein, Claes Rudberg, Lars Rudberg, Magnus Ruth, Rune Sandbu, Bengt Sandhammar, Ingemar Sandin, Björn Sandmark, José Santos, Runa Schedwin, Eric Secher, Ralf Segersvärd, Håkan Sellström, Charles Silseth, Göran Simert, Björn Sjöström, Johnny Sobin, Stefan Spinnell, Roger Stenling, Rolf Stjernman, Edit Stöckel, Dag Stockeld, Nils Stormby, Kaj Strid, Arild Stubberöd, Erik Svartholm, Conny Svensson, Jan-Olov Svensson, Anders Sylvan, Maria Sylvan, Kalev Teder, Kjell Thor, Lars Thulin, Orjan Tjernström, Torbjörn Tuvesson, Egil Tveit, Tadeusz Tyszkiewicz, Maciej Tytov, Sören Vallgren, Anders Victorin, Gunnar Wagenius, Torkel Wallin, Bruno Walther, Johan Wennerberg, Ingmar Wennström, Jens Wigermark, Olle Wihlborg, Bo Wikström, Erik Wilander, Bo Wilhelmsson, Roger Willén, and Mats Wirén.

    • Grant Support: By grant R01 CA57947-03 from the National Cancer Institute and by the Swedish Cancer Society (Drs. Lagergren and Nyrén).

    • Requests for Single Reprints: Jesper Lagergren, MD, PhD, Department of Medical Epidemiology, Karolinska Institutet, Box 281, SE-171 77 Stockholm, Sweden; e-mail, jesper.lagergren{at}mep.ki.se.

    • Requests To Purchase Bulk Reprints (minimum, 100 copies): the Reprints Coordinator; phone, 215-351-2657; e-mail, reprints{at}mail.acponline.org.

    • Current Author Addresses: Drs. Lagergren, Adami, and Nyrén: Department of Medical Epidemiology, Karolinska Institutet, Box 281, SE-171 77 Stockholm, Sweden.

    • Author Contributions: Conception and design: J. Lagergren, H.-O. Adami, O. Nyrén.

    • Analysis and interpretation of the data: J. Lagergren, R. Bergström, O. Nyrén.

    • Drafting of the article: J. Lagergren, O. Nyrén.

    • Critical revision of the article for important intellectual content: J. Lagergren, R. Bergström, H.-O. Adami, O. Nyrén.

    • Final approval of the article: J. Lagergren, H.-O. Adami, O. Nyrén.

    • Provision of study materials or patients: J. Lagergren, O. Nyrén.

    • Statistical expertise: J. Lagergren, R. Bergström, O. Nyrén.

    • Obtaining of funding: J. Lagergren, H.-O. Adami, O. Nyrén.

    • Administrative, technical, or logistic support: J. Lagergren, O. Nyrén.

    • Collection and assembly of data: J. Lagergren, O. Nyrén.

    Summary for Patients

    • Summaries for Patients:The Association between Use of Certain Medicines and Cancer of the Esophagus Ann Intern Med August 1, 2000 133:165
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    1. Ann Intern Med August 1, 2000 vol. 133 no. 3 165-175
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